Olanzapine I is an orally active, potent, antipsychotic agent. ##STR1## It is commercially available as Zyprexa.RTM. from Eli Lilly Co. The antipsychotic effect of olanzapine is ascribed by the literature to blocking of the dopamine D.sub.2 receptor and to 5-HT antagonism.
One of the main serum metabolites of olanzapine is olanzapine-4'-N-oxide II, formed by oxidation of the nitrogen at the 4-position of the piperazinyl ring. The chemical name of II is 2-methyl-4-(4-methyl-4-oxido-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodia zepine and hereinafter is referred to as olanzapine-N-oxide. ##STR2##
Because olanzapine is oxidized to olanzapine-N-oxide in the liver by P450 enzymes, drug-drug interactions arise from the concomitant administration of other drugs that stimulate or inhibit P450 or rely on P450 enzymes for their disposition. The human liver flavin-containing monooxygenase (FMO3) is involved in the metabolism of olanzapine-N-oxide. Exemplary drugs metabolized by the FMO3 enzyme include cimetidine and tamoxifen.
It is therefore desirable to find a compound with the advantages of olanzapine which would provide a more predictable dosage regimen in the patient population and that would decrease the chances for drug-drug interaction.